We propose that mast cell regulation of immune responses in EAE (and by extension, MS) occurs through several mechanisms. These include: a) alteration of the blood-brain barrier to facilitate entry of autoreactive T cells;b) release of pro-inflammatory cytokines such as TNF-a;c) regulation of T cell trafficking via chemokine expression or modulation of homing receptors;d) release of regulatory cytokines such as IL-4 and IL-10 to modulate an ongoing response;e) and direct damage of the myelin sheath through release of proteases/cytokines that contribute to "epitope spreading" by releasing new antigen epitopes for presentation to T cells. In this application, we will use an established model of relapsing-remitting multiple sclerosis to examine some of the potential mechanisms that underlie mast cell effects on a disease course.